Temporal lobe epilepsy (TLE) is characterized by focal seizures arising from limbic structures including the hippocampus. Partial temporal lobe seizures often cause functional deficits beyond those expected from local hippocampal impairment. In addition to amnesia, patients typically exhibit impaired consciousness. In humans, focal temporal lobe seizures associated with impaired consciousness are positively correlated with 1-2 Hz ictal neocortical slow waves on electroencephalography (EEG) and decreased cerebral blood flow (CBF) in the neocortex. It is unknown how a focal seizure in the limbic system (including the hippocampus) creates ictal slowing in the neocortex and impaired consciousness. Preliminary data suggests that subcortical structures play an important role in both seizure activity and neocortical slowing. Our central hypothesis is that focal hippocampal seizures propagate to nuclei that inhibit subcortical arousal systems, leading to depressed function in the neocortex. We plan to investigate this phenomenon through a combination of neuroimaging, electrophysiology, and neurotransmitter techniques using a rodent model of focal hippocampal seizures. Our first aim will be to map the cortical and subcortical networks underlying ictal neocortical slow activity. We will accomplish this by imaging rodents during limbic seizures using blood oxygen level dependent (BOLD) fMRI. Once we have identified candidate regions involved in the network governing neocortical slowing, our second aim will be to probe the newly identified structures. In this aim, we will use electrophysiology techniques to record directly from, stimulate, disconnect, and inactivate candidate regions to determine which are critical for neocortical slow activity. Our third aim will be to identify neurotransmitter changes underlying ictal neocortical slow activity. Using our rodent model of partial temporal lobe epilepsy, we will measure neurotransmitter levels with biosensor probes to determine if activating neurotransmitters decrease in the neocortex during ictal slow activity. We will then reverse/create ictal neocortical slowing by local infusion of specific neurotransmitter agonists/antagonists. Impaired neocortical function and cognitive deficits significantly reduce the quality of life in patients with TLE. Understanding the fundamental mechanisms of remote network impairment in focal epilepsy may lead to improved surgical, neurostimulation or pharmacotherapies for this disorder. PUBLIC HEALTH RELEVANCE: Impaired consciousness and cortical dysfunction during temporal lobe seizures causes motor vehicle accidents, drowning, poor work and school performance, and social stigmatization. Through understanding the underlying mechanisms of complex partial temporal lobe seizures, we may successfully design therapies to preserve consciousness and improve patient quality of life.